Process for hydrolyzing 16, 17 steroid acetonides



United States Patent 3,021,347 PROCESS FOR HYDROLYZING 16,17 STEROID ACETONIDES George R. Allen, Evansville, Ind., and Michael Marx, Leonia, and Martin J. Weiss, Oratlell, N.J., assignors to American Cyanamid Company, New York, N.Y.,

a corporation of Maine No Drawing. Filed Oct. 13, 1959, Ser. No. 846,054

6 Claims. (Cl. 260-39145) This invention relates to a process for hydrolyzing '16,17-substituted methylenedioxy steroids to the corresponding 16,l7-dihydroxy steroids.

In the prior art various attempts to hydrolyze 16,17- steroid acetonides have met with failure: G. Cooley et al., J. Chem. 800., p. 4373 (1955); J. Fried et al., J. Am. Chem. Soc. 80, p. 2338 (1958).

We have now found that the 16,17-substituted methylenedioxy steroids can be hydrolyzed to the corresponding 16,17-dihydroxy steroids by theuse of acids having a particular pKa value in the presence of a sutficient amount of water as described hereinafter.

The reaction which takes place in ring D ofv the steroid nucleus can be illustrated as follows:

in which R is hydrogen or a hydroxyl or lower alkanoyloxy radical; R and R are hydrogen or lower alkyl radicals, and R is hydrogen or a hydroxyl radical.

The process of the present invention is carried out by heating the 16,17-substituted methylenedioxy steroid in the presence of an acid having an acid dissociation constant (determined at 25 C.) within the range of IX to l lO- and a concentration in water of from 20 to 60% acid. While the hydrolysis will take place within the above range, it is preferred that the range be from 40% to 60% acid. The mixture is heated at a temperature within the range of 50 to 110 C. for a period of from 10 minutes to 12 hours.

' The -16,-17-steroid acetonides of the present invention used as starting material can be for example 1611:,17oz-isopropylidenedioxy progesterone;

1 6a, l7a-isopropylidenedioxy- 1 ,4-pregnadiene-3,20-dione;

4-bromo-16a,17a-isopropylidenedioxy-1,4-pregnadiene- 3,20-dione;

16a,17a-isopropylidenedioxy-4,9(1l)-pregnadiene-3,20-

dione;

9cz-flL1010-1 6oz, l7a-isopropylidenedioxy-1 15,21-dihydroxy- 1,4-pregnadiene-3,20-dione;

9a-fluoro-16a,l7a-isopropylidenedioxy-1l5-hydroxy-1,4-

pregnadiene-3,20-dione;

9a-fiuoro-16a,l7a-isopropylidenedioxy-1 -hydroxy-4- pregnene-3,20-dione;

9a-fiuoro-l6a,17a-isopropylidenedioxy-115,21-dihydroxy- 4-pregnene-3,20-dione;

Qa-bromo-l 1 5-hydroxyl 60:, 1 7a-isopropylidenedioxy-4- pregnene-3,20-dione;

9a-bromo-1 l5-hydroxy- 1 6oz, 17a-isopropy1idenedioxy-4- pregnene-3,20-dione;

1 l 5,2l-dihydroxy-16a,l7a-isopropylidenedioxy-4-pregnene-3 ,ZO-dione;

9a-chloro-1 15-hydroxy-160:,17a-isopropylidenedioxy- 1 ,4-

pregnadiene-3,20-dione; I

9a-fluoro-16a,l7u-isopropylidenedioxy-1,4-pregnadiene- 3,11,20-trione;

"ice

and the like. The preparation of these starting materials is described and claimed in an application of one of us, Serial No. 720,564,-filed March 11, 1958, and a continuation in part application, Serial No. 742,742 filed June 18, 1958. The general method of these latter applications is the reaction of a l6a,17a-dihydroxy steroids with an alkanal or an alkanone in the presence of a mineral acid. When the reaction is complete, the product is recovered from the reaction mixture by well known means such as cooling the mixture and diluting with water to precipitate the product. 'The product can be further purified by crystallization from organic solvents.

. The 16,17-dihydroxy steroids prepared by the process of the present invention are well known for their glucocorticoid activity, natriuresis and progestational activity. Compounds such as triamcinolone are included in this "group. The process of the present invention can be used as the final steps in the purification of 16,17-dihydroxy 40 .steroids whereby the acetonides are prepared and separated from impurities and then the 16,17-dihydroxy steroids reconstituted by the present process. The following examples illustrate the process of hydrolyzing 16,17-steroid acetonides to the corresponding 16,17-dihydroxy steroids.

EXAMPLE I Preparation of .I60 ,1 7oc-dihydr0xypr0gester0ne One ,grarn of 16a,17a isopropylidenedioxyprogesterone 'and 30 ml. of formic acid (acid dissociation constant=2.l4 1()* are heated on the steam-bath for 30 minutes. The hot solution is then diluted to turbidity with water and cooled to give the product which is re- 55 crystallized from methylene chloride-petroleum ether.

Melting point 2l9223 C.; [a] -|-92 (c 1.04, chloroform) and max. 241 my. (e=l6,100). The yield is 63%.

EXAMPLE II Preparation of 160:,17a-dihydr0xy-1,4-pregnadiene- 3,20-di0r ze 3 EXAMPLE III Preparation of 160a,] 7a-dihydr0xy-1,4-pregnadiene 3,20-

dione One gram of 16a,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione and 55 ml. of acetic acid-water solution (the acid dissociation constant of acetic acid is l.86 l" in the proportion of 5 parts of acetic acid to 4 parts of water are allowed to reflux for 6 hours. After this time, the hot solution is diluted to turbidity with water and cooled to give the product which is recrystallized from acetone-petroleum ether. This is a product identical with that of Example II. The yield is 26%.

EXAMPLE IV Preparation of 4-br0mo 1611,17m dihydroxy-L4-pregnadiene-3,20-di0ne One gram of 4-bromo 161,170; isopropylidenedioxy- 1,4-pregnadiene-3,20-dione and 55 ml. of 5:4 acetic acid- Water solution are refluxed for 6 hours. The hot solution is then diluted to turbidity with water and cooled to give the product which is recrystallized to yield white needles, melting point 227229 C.; [a] 2l.5 (c 1.1, chloroform); max. 244 mu (e==15,300); A max. 3.00, 5.88, 6.02, 626 yield 50%.

EXAMPLE V Preparation of 160:,1711 dihydroxy-Z,4-pregnadiene-3,20-

dione One gram of 16oz,l7a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione and 55 ml. of 5:4 acetic acid-water solution are refluxed for 6 hours. The solution is concentrated to about one-half volume and slowly diluted with water to turbidity while hot. The solution is then cooled to give 0.33 g. of near white crystals; melting point 182-190 C. after sintering at 170 C. This material is recrystallized from acetone-petroleum ether to give 0.145 g. of white needles melting at 209-21l C.

EXAMPLE VI Preparation of 16,17u dihydroxy-4,9(11)-pregnadiene- 3,20-dione Preparation of 9a-fluoro 11B,16a,17u,21 tetrahydroxy- 1,4-pregnadiene-3,ZO-dione (triamcinolone) 9a-fluoro 160:,170: isopropylidenedioxy-l1,8,21-dihydroxy-1,4-pregnadiene-3,20-dione (0.357 g.) and ml.

of 60% formic acid are heated on the steam-bath for 30 minutes. A small amount of undissolved solid is removed by filtration and the hot filtrate is diluted to turbidity with water. The solution is chilled and filtered to give 0.102 g. of white solid melting at 250260 C. dec. An additional 98' mg. of solid is recovered from the filtrate.

EXAMPLE VIII 9a-fluoro-16a,17a-isopropylidenedioxy -11,9 hydroxy- 1,4-pregnadiene-3,20-dione (0.797 g.) and ml. of 60% formic acid are heated on the steam-bath for 30 minutes. A small amount of undissolved material remains. The solvents are removed under reduced pressure on the steam-bath, and the residue is distributed between 100 Preparation. of

ml. of water and ml. of methylene chloride. The methylene chloride solution is dried over magnesium sulfate and taken to dryness to give 0.669 g. of product.

In the preceding examples all melting points were determined in a capillary tube and are uncorrected. The ultraviolet spectra were determined in methanol solution on a Cary recording spectrophotometer. The infrared spectra (pressed potassium bromide disc) were determined With a Perkin-Elmer spectrophotometer (model 21). Optical rotations were determined in a l-dm. semimicro tube, and all evaporations were carried out under reduced pressure unless otherwise specified. Except where otherwise noted, the petroleum ether used was that fraction boiling at 6070.

We claim:

1. A method of preparing 9oc-fll101'0-11B,16ot,170t,21- tetrahydroxy-1,4-pregnadiene-3,ZO-dione' which comprises heating to a temperature within the range of 50 to C. 9a-fluoro-161x,l7a-isopropylidenedioxy-1118,2l-dihydroxy-1,4-pregnadiene 3,20 dione with an aqueous formic acid solution consisting of not less than 20% and not more than 60% formic acid the remainder of the aqueous acid solution being water.

2. A method of preparing 16a,l7a-dihydroxy-4,9(11)- pregnadieneGJO-dione which comprises heating to a temperature within the range of 50 to 110 C. 16a,l7oc-l50- propylide'nedioxy-4,9 1 1 )-pregnadiene-3,20-dione with an aqueous formic acid solution containing not less than 20% and not more than 60% formic acid the remainder consisting of water.

3. A method of preparing 9a-fluoro-11B,16u,17a-trihydroxy-l,4-pregnadiene-3,20-dione which comprises heating to a temperature within the range of 50 to 110 C. 9afluoro-16a,17a-isopropylidenedioxy 1,4 pregnadiene- 3,20-dione with an aqueous formic acid solution containing not less than 20% and not more than 60% of formic acid the remainder consisting of water.

4. A method of preparing compounds of the formula:

and

radicals and -C -C is a divalentradical of the group consisting of CH -CH and -CH=CH- radicals which comprises heating to a temperature within the range of 50 to 110 C., a steroid having the formula:

4 Or T wherein R is a member of the group consisting of hydrogen, hydroxyl and lower alkanoylo'xy' radicals, R and R 5 6 are members of the group consisting of hydrogen and 6. A method in accordance with claim 4 in which the lower alkyl radicals and lower fatty acid is acetic acid.

0 c References Cited in the file of this patent I 5 UNITED STATES PATENTS and -C C are as defined above, and a lower fatty 2 345 216 Reichstein Man 28 19.44

acid, said acid being present in an amount within the range of 20 to 60%, the remainder consisting of water. OTHER REFERENCES 5. A method in accordance with claim 4 in which the Mills et a1.: 1. Am. Chem. Soc., vol 81( March 5, 1959), lower fatty acid is formic acid. 10 pages 1264 and 1265 (page 1264 necessary). 

4. A METHOD OF PREPARING COMPOUNDS OF THE FORMULA: 